The Laboratory is investigating: Animals, cell culture models, and human tissues to characterize variations in proteins (expressed gene products) in: neural aging, trauma, degeneration; and in normal physiological events, such as circadian rhythms and hibernation. Studies using a rat model for Alzheimer's disease (AD) have shown that a rapid, persistent, and reversible induction of amyloid precursor protein (ALP) occurs in response to the loss of subcortical innervation. Despite the induction of rapid ALP turnover, elevated secretion of ALP into the CSF, and elevation of the beta-A4 peptide, senile plaques are not found in the brains of these animals which suggests that an increase in beta-A4 alone is not sufficient to cause senile plaques. In addition to senile plaques, heat shock proteins (stress protein*) are also increased in AD patients. To understand the role of stress proteins in neurodegeneration, we have preconditioned neuronal PC 12 cells by submaximal heat shock. Using these preconditioned cells, we have shown that stress proteins can protect cells from heat shock-related alterations, including protection from the loss of neurites and abnormal phosphorylation of tau to form A68, the primary constituent of neurofibrillary tangles in AD. In studies of nerve damage and human neurodegenerative disorders we have shown that apolipoprotein E (apoE) is elevated in plasma. The role of apoE in nerve regeneration is being investigated in neuronal PC 12 cells. Additional proteins, such as alpha-2 haptoglobin and fibrinogen have been found to be elevated in the CSF of patients with AD and schizophrenia. Both of these proteins are acute phase proteins, and these findings may indicate an inflammatory response in the CNS in these diseases. The Laboratory is continuing to search for additional proteins associated with neurodegeneration with high resolution two- dimensional protein electrophoresis and computerized image analysis. To study endogenous mechanisms within the brain which may protect against cerebral ischemia and stroke, we are identifying proteins associated with ischemic levels of blood flow seen in the hibernating ground squirrel. In addition, normal protein changes associated with circadian pacemakers are being identified in several animal model systems.